Ebola and Priorities in Drug Development

Judy Stone, MD is an infectious disease specialist, experienced in conducting clinical research. She is the author of Conducting Clinical Research, the essential guide to the topic. She survived 25 years in solo practice in rural Cumberland, Maryland, and is now broadening her horizons. She particularly loves writing about ethical issues, and tilting at windmills in her advocacy for social justice. As part of her overall desire to save the world when she grows up, she has become especially interested in neglected tropical diseases. When not slaving over hot patients, she can be found playing with photography, friends’ dogs, or in her garden. Follow on Twitter @drjudystone or on her website. Follow on Twitter @drjudystone.

Judy Stone, MD is an infectious disease specialist, experienced in conducting clinical research. She is the author of Conducting Clinical Research, the essential guide to the topic. She survived 25 years in solo practice in rural Cumberland, Maryland, and is now broadening her horizons. She particularly loves writing about ethical issues, and tilting at windmills in her advocacy for social justice. As part of her overall desire to save the world when she grows up, she has become especially interested in neglected tropical diseases. When not slaving over hot patients, she can be found playing with photography, friends’ dogs, or in her garden. Follow on Twitter @drjudystone or on her website. Follow on Twitter @drjudystone.

The only way I can see this happening is by either the “animal rule,⁠” where the FDA allows animal data to be used when clinical trials of efficacy are not practical, after safety testing is done in healthy volunteers (Phase 1, first in human) or by a “compassionate use,” when a drug’s use is allowed out of desperation, where there are no alternatives.

There are several candidate treatments for Ebola:

Tekmira has an RNA interference drug in Phase 1 testing, but further testing was put on hold while the FDA was examining data about cytokine release, which could be deadly. (This is what happened in the disastrous TeGenero trial⁠, where six healthy volunteers became critically ill with multi-organ failure from cytokine release).

This older treatment—transfusion of “convalescent serum” from patients who have recovered from the same illness—seems obvious. This was used successfully to treat influenza in the 1918⁠ pandemic, polio in 1934⁠, and measles, among others. Transfusions were tried in the Kikwit Ebola outbreak in 1995⁠, with apparently good results. The problem is these patients also received better supportive care, muddying the conclusions. Dr. Thomas Geisbert, an expert on Ebola virus at The University of Texas Medical Branch at Galveston, did not see the same good outcome in studies with rhesus macaques infected with Ebola, but these were small numbers. Given the long-standing successful history, the option of convalescent serum transfusion still seems worth pursuing as a potential, relatively low-tech treatment, at least in crisis situations like we have now.

Vaccines are also under development for Ebola. They will measure antibody response as a surrogate marker for efficacy—it would be hugely unethical to expose volunteers to the disease to test for protection from the vaccine. Dr. Geisbert is particularly enthusiastic about a recombinant vaccine. He has demonstrated use of a vesicular stomatitis vector⁠ to deliver the Ebola glycoprotein antigen to be moderately effective in animal models, even when given soon after exposure to the virus. This is similar to the way rabies vaccine is produced, he explained. Profectus⁠ is using this approach for treatments for a variety of viral pathogens.

One issue with vaccines is the question of what the source⁠ is. Live-attenuated vaccines (e.g., oral polio, measles) are the most effective, prompting a more robust immune response. Although they are weakened and are not dangerous, they tend to have more side effects than killed vaccines. There would likely be a lack of enthusiasm for one for hemorrhagic fevers. Killed vaccines (like influenza) have fewer side effects, but tend to require boosters.

Another problem is how to determine the effectiveness of the vaccine in the field. That could be done during an outbreak, offering the vaccine to some, but not others. There would certainly be an ethical outcry over that, although it is unknown whether the vaccine actually works. There are huge logistical concerns in doing a trial during an outbreak, as well as ethical concerns over the adequacy of consent. (A prime example was the suit against Pfizer over its use of Trovafloxacin⁠ in Nigeria during the midst of an epidemic of meningococcal meningitis.)

Widespread use of an Ebola vaccine among Africans will never occur—the disease occurs sporadically and infrequently. There were also cultural aversions to vaccines, even before the CIA’s vaccine ruse while seeking Bin Laden fueled mistrust and has led to a resurgence of polio. Any vaccine would be too costly, and there are other illnesses, such as measles and polio, that are far more important to target. Vaccines are likely to be used in two scenarios. One is for ring vaccination⁠ of exposed individuals, to prevent further spread. The other is pre-exposure vaccination of healthcare workers, as is done with hepatitis.

It’s important to remember that supportive care is vitally important. I was an investigator on a number of trials for sepsis drugs and, while none were shown to be effective, our mortality dropped from the predicted ~50%, to 10-15%. I emphasize—none of these drugs worked. Rather, we learned how to better manage critically ill, septic patients, thereby drastically reducing our mortality.

Some of the hurdles to be overcome follow.

Priorities and ethics

Perhaps the biggest problem in developing drugs for hemorrhagic fevers is that they occur infrequently, akin to rare diseases in the U.S., and therefore there is not much awareness of them. They don’t affect us, except from concerns over bioterrorism. More importantly, in a purely crass sense, they affect poor people, mostly in Africa. Drugs for illnesses there will not be profitable, therefore pharmaceutical companies don’t bother investing in the necessary drug development. This is the same problem affecting development of drugs for neglected tropical diseases (NTDs)⁠, which primarily affect poor, disenfranchised people. In fact, there are large swaths of America affected by many of these same illnesses, especially in the South, the Texas borderlands, and Appalachia, yet they receive similarly little attention and no public outcry.

The justifiable outrage that drugs are not being developed for poor people because they will not be profitable for pharma’s investors needs to be put in perspective with other drugs for bioterrorism and especially with the crisis in antibiotic development.

Ironically, because of profit incentives, a valuable medicine was unavailable last year in the U.S., while it was widely available in Europe. The vaccine, Novartis’ Bexsero, is effective against the strain of meningococcal meningitis that caused an epidemic in Princeton and Santa Barbara. That strain is serogroup B, and is not covered by the vaccines marketed in the U.S. Per the NY Times, “’Novartis had decided there wasn’t enough of a market for it here,” said Jason Schwartz, a fellow at the Princeton University Center for Human Values and an expert in vaccine policy. He added that it did not make sense for Novartis to spend millions of dollars to license a vaccine that would most likely be used only in scattershot outbreaks in the United States.”

President George Bush signed project Bioshield, which earmarked $5.6 billion for new drugs and vaccines to counter bioterrorism, in 2004. One of its beneficiaries is Emergent BioSolutions, which holds a lucrative and exclusive contract for anthrax vaccine⁠ production. I was particularly disturbed by its successful proposal to conduct pediatric anthrax vaccine trials. It has since won other juicy biodefense contracts⁠.

While identifying effective treatment for Ebola is important, we should not forget the many multi-drug resistant infections that do not have treatments as well, and the frighteningly high and increasing toll MDR infections have both in the U.S. and globally. The lack of attention focused on antibiotic development is very disturbing.

I believe we need to develop drugs for infections globally, especially those transmitted person-to-person (unlike anthrax). If the private market won’t address the problems of drugs for important diseases affecting public health, perhaps governments worldwide should fund development of these drugs. Imagine if there were such collaboration.

About the Author:Judy Stone, MD is an infectious disease specialist, experienced in conducting clinical research. She is the author of Conducting Clinical Research, the essential guide to the topic. She survived 25 years in solo practice in rural Cumberland, Maryland, and is now broadening her horizons. She particularly loves writing about ethical issues, and tilting at windmills in her advocacy for social justice. As part of her overall desire to save the world when she grows up, she has become especially interested in neglected tropical diseases. When not slaving over hot patients, she can be found playing with photography, friends’ dogs, or in her garden. Follow on Twitter @drjudystone or on her website. Follow on Twitter @drjudystone.

1 Comment

Our first priority is and there is no question about it, unless you are related closer to pawians then to homo sapiens, to dislocate health care from Wall street… medical care should be freely available, pharma companies should be managed by public trusts with open doors research, needless to say copyrights are screwed but either way Napster for Novartis and Co is already there and it is only question of time when you can download the drug you need via torrent… so buy buy Novartis (by the way if you expect pity from a Swiss based company, you may need to wait rather long as the Swiss banks have shown)… and last but not least WHO should move to open sky offices in Africa and not dwell in luminous Swiss palaces.